Bailey & Phillips Research Group
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The tetrahydro-β-carboline moiety is a sub-structure common to hundreds of indole alkaloids natural products, including the intricate cage-like (+)-ajmaline, an anti-arrhythmic agent obtained from the roots of Rauwolfia serpentine, an evergreen shrub found in tropical regions.
images © dinesh valke and used with permission
A major synthetic problem has been accessing the cis-1,3-disubstituted derivatives required for (+)-ajmaline and related natural products, such as (−)-raumacline and (−)-suaveoline.
By a careful study of the mechanism of the Pictet-Spengler reaction, we developed the first general (and asymmetric) route to cis-1,3-disubstituted tetrahydro-β-carbolines, starting from L-tryptophan.1,2 We have found that some reagent pairings give exceptional cis-selectivity in this kinetically controlled Pictet-Spengler reaction (Scheme 1) and we have applied this to the synthesis of several natural products and analogues, including the total synthesis of (−)-suaveoline.3
Scheme 1 - cis-selective Pictet Spengler reaction
We have developed a synthetic route to the ajmaline family of indole alkaloids which selectively introduces four of the chiral centres required for both (−)-raumacline and (+)-ajmaline through the use of a cis-selective Pictet Spengler reaction (Scheme 1), which installs the stereochemistry at C3 and a Michael reaction/lactonisation sequence (Scheme 2) which selectively installs the key stereochemistry at C15 and C16.
Scheme 2 - Michael reaction / lactonisation sequence
We have applied this methodology in our total synthesis of (−)-raumacline4 and are also using it in ongoing work towards (+)-ajmaline.
- P. D. Bailey, S. P. Hollinshead, N. R. McLay, K. M. Morgan, S. J. Palmer, S. N. Prince, C. D. Reynolds and S. D. Wood, J. Chem. Soc. Perkin Trans. 1, 1993, 431-439. DOI
- L. Alberch, P. D. Bailey, P. D. Clingan, T. J. Mills, R. A. Price and R. G. Pritchard, Eur. J. Org. Chem., 2004, 1887. DOI
- P. D. Bailey, and K. M. Morgan, J. Chem. Soc., Perkin Trans. 1, 2000, 3578. DOI
- P. D. Bailey, P. D. Clingan, T. J. Mills, R. A. Price and R. G. Pritchard, Chem. Commun., 2003, 2800. DOI